Mutations in the gene encoding KRAS, a small GTPase that mediates growth factor receptor signaling, are implicated in colorectal, lung, and pancreatic cancers, yet KRAS has proven an unsuccessful pharmacological target. Kim et al. cataloged KRAS mutations in more than 100 non-small cell lung cancer (NSCLC)–derived cell lines and performed whole-genome mRNA expression analysis to identify potential synthetic-lethal genetic interactions with mutant KRAS. The authors then screened for short inhibitory RNAs (siRNAs) that reduced the viability of a KRAS mutant colorectal cancer cell line and found that siRNAs targeting genes encoding components of the nuclear export machinery, including XPO1, were the most effective. Targeting XPO1 in more than 50 KRAS mutant cell lines reduced their viability. The clinically available XPO1 inhibitor KPT-330 increased apoptosis in KRAS mutant cells. Tumor volumes in three mouse models of KRAS mutant–driven cancers were markedly reduced by KPT-330 compared with those in untreated mice. Inhibition of XPO1 in cultured cells led to nuclear accumulation of the nuclear factor κB (NF-κB) inhibitory protein IκBα. Knockdown of the gene encoding IκBα rendered the KRAS mutant cells resistant to the XPO1 inhibitor, suggesting that KRAS mutant cells rely on the continual nuclear export of IκBα to enable NF-κB–dependent signaling and cell survival. A small number of NSCLC cell lines that were relatively resistant to XPO1 inhibitors had mutations in FSTL5. FSTL5 is implicated as a tumor suppressor protein in hepatocellular carcinoma, a cancer that is often associated with the transcriptional regulator YAP1. Deletion of FSTL5 in cell lines led to increased YAP1 abundance, and sequencing analysis and immunostaining of KRAS mutant lung adenocarcinoma specimens showed a positive correlation between the occurrence of FSTL5 mutations and the abundance of YAP1. Finally, chemical or genetic targeting of YAP1 rendered KPT-330–resistant cell lines sensitive to this XPO1 inhibitor. Together, these data suggest that XPO1 is a druggable target in KRAS mutant lung cancers, but that patients should also be screened for other mutations, such as in FSTL5, that may affect efficacy.